Process of manufacturing 16-methylene reichstein&#39;s compound s and intermediates obtained therein



United States Patent PROCESS OF MANUFACTURING 16-METHYLENE REICHSTEINS COMPOUND S AND INTERME- DIATES OBTAINED THEREIN Fritz Von Werder, Klaus Bruckner, and Karl-Heinz Bork,

Darmstadt, Germany, assignors to E. Merck Aktiengesellschaft, Darmstadt, Germany, a corporation of Germany No Drawing. Filed May 11, 1960, Ser. No. 28,194 Claims priority, application Germany, May 22, 1959,

M 41,596 12 Claims. (Cl. 260397.4)

The present invention relates to a process for the manufacture of the 16-methylene derivative of compound S (16-methylene-4-pregnene-17a,21-dio1-3,20-dione) and its esters and to certain intermediates produced in the course of such process.

The alkylated corticoids have recently gained increasing importance in human medicine. 16-methylene-Reichsteins compound S is related to one group of such alkylated corticoids and is convertible thereinto. Therefore an efiicient synthesis for this steroid is of considerable commercial importance.

The present invention provides a technically useful synthesis for 16-methylene-Reichsteins compound S in good yields.

We have found that 1G-methyIene-Reichsteins compound S may be prepared in steps, starting either from 16a,17a-oXido-16,6-methyl-5-pregnene-3B-ol-ZO-one (I) or from 16-methyl-4,16-pregnadiene-3,20-dione (II). Compound I may be converted by Oppenauer oxidation, and

compound II by epoxidation into 1604,1711 -oxido- 16B- methyl-4-pregnene-3,ZO-dione (III). It was surprising that the oxido ring of compound III could be opened by treatment with an acid to form the 16-methylene-4-pregnene- 17u-ol-3,20-dione (IV). Compound IV can then be converted into 16-methylene-Reichsteins compound S by introduction of a 21-iodine group, followed by treatment with an alkali metal acetate or hydroxide and subsequent saponification, if desired, of the ester produced by use of the alkali metal organic salt.

According to our invention a method of manufacturing 16-methylene-Reichsteins compound S is provided which comprises the steps of dehydrogenating 16a,17a-0xido- 16/8-methyl-5-pregnene-3fl-ol-20-one (I) by Oppenauer reaction, or reacting 16-methyl-4,16-pregnadiene-3,20-dione (II) with an alkaline solution of H 0 or with an organic per-acid, to form in each case 1606,17tZ-OXldOr16fl-Hl8thYl- 4-pregnene-3,20-dione (III); reacting III with an acid in an inert solvent, such as benzene, to form 16-methylene- 4-'pregnene-l7u-ol-3,20-dione (1V); reacting IV with an alkaline solution of iodine to form 21-iodo-16-methylene- 4-pregnene-17a-ol-3,20-dione (V); reacting V with an alkali acetate to form 16-methylene-4-pregnene-17a,21-diol- 3,20-dione 21-acetate (VI); and saponifying VI, if desired, to obtain 16-methylene-Reichsteins compound S.

The process of the invention is graphically illustrated by the following structural equations:

was

The conversion of the oxido compound I into the ketone III is conducted according to the usual methods of Oppenauer dehydrogenation, for example, by treatment with aluminum isopropylate in a toluene solution containing cyclohexanone.

The diene II may be converted into the oxido compound III, for example, by treatment with a mixture of H 0 (30%) and aqueous K CO The epoxidation of II can also be effected by treatment with peracid, c.g. with an ethereal solution-of phthalic monoperoxy-acid.

A very important step in the present process is the opening of the oxido ring in compound III by treatment with a preferably strong acid in an inert solvent. Particularly suitable are catalytic amounts of a strong acid, for example, -a sulfonic acid, such as p-toluene-sulfonic acid or benzene sulfonic acid. The solvent is preferably benzene. This opening of a 16/3-methyl-16,17-oxido steroid resulting in the formation 0 fa 16-methylene group was surprisiing and unexpected. The yields of these reactions are goo The 16-methylene-4-pregnene-17a-ol-3,20-dione (IV) obtained may be converted into the l2-iodide (V) by treatment with an alkaline solution of iodine. The iodine is preferably added in small portions to a solution of compound IV in an inert solvent, such as tetrahydrofuran. Then an aqueous solution of NaOH (10%) is added with stirring until the color of the iodine has disappeared.

By treatment with an alkali acct-ate the iodide V may be converted into 16-methylene-Reichsteins compound S 21-acetate (VI). This acetylation may be carried out in a solution of acetone with potassium acetate.

The ester VI may be saponified in the usual way to 16-methylene-Reichsteins compound S. The saponification may be carried out in a solution of KHCO in methanol.

The starting material, the oxido compound I, may be prepared by treatment of l6-methyl-5,16-pregnadiene-3- ol-20-one 3-acetate (described by Wettstein, Helv. Chim. Acta., vol. 27, p. 1803 (1944) with H in an alkaline medium.

The starting compound II may be prepared by addition of diazomethane to 16-dehydroprogesterone and pyrolysis of the pyrazoline derivative obtained.

Example.16-methylene compound S (A-1) 16 3 methyl 16a,17a oxido-4-pregnene-3,20- dione.From a solution of 50 g. of 16B-methyl-l6a,17moxido-5-pregnene-3B-ol-20-one (I) (M.P. l85186, (a) in chloroform=-25) in a mixture of 400 ml. of cyclohexanone and 2.5 1. of toluene, 400 ml. of the solvent are evaporated at normal pressure. The residue is treated with 50 g. of aluminum isopropylate and refluxed for 2. hours. After treatment with steam the remaining solution is filtered through kieselguhr with suction. The residue in the filter is boiled several times with chloroform. The chloroform extracts are washed with sulfuric acid (3% Na CO (3%) and water, dried over CaCl filtered and concentrated in vacuo The residue is recrystallized from methanol. l6 3-methyl-16a,17a-oxido-4-pregnene-3,20-dione (III) yields colorless crystals with a melting point of 159-161", (a) in chloroform 151.5".

k 240 m Ei'i' 514 (Alcohol) (A-2) 1613 methyl 1611,17u-0xido-4-pregnene-3,20- di0ne.-To a solution of 20 g. of 16-methyl-16-dehydroprogesterone (II) in 5 l. of methanol, cooled to 0, are added 220 ml. of H 0 (30%) and a solution of 5.1 g. K CO in 250 ml. of water. After 8 hours the solution is neutralized with acetic acid, concentrated in vacuo and poured into water. After recrystallization from methanol the 16B-methyl-l6a,17a-oxido-4-pregnene-3,ZO-dione obtained melts at 161.

(A-3) 16B methyl 16a,l7a-0xid0-4-pregnene-3,20- di0ne.--10 g. of 16-methyl-16-dehydroprogesterone are dissolved in 500 ml. of anhydrous chloroform. At -60 C. 1.1 equivalents of an ethereal phthalic monopero-xyacid solution are added. After several hours the solution is heated to 0", and allowed to stand for 1-2 days at this temperature. The solution is washed with a solution of FeSO with water, with a solution of NaHCO and finally again with water, dried and evaporated. The residue is recrystallized from methanol. The obtained 16,8-

metl61yl-16a,l7'a-oxido-4-pregnene-3,20-dione (III) melts at 1 1.

(B) 16 methylene 4-pregnene-17m-0l-3,20-di0ne.-- 34 g. of 16-methy1-16a,17u-0xid0-4-pregnene-3,ZO-dione are dissolved in a mixture of 1.2 l. of benzene. From this solution, 240 ml. of the solvent are evaporated. The residue is treated with 2.4 g. of p-toluene-sulfonic acid and boiled: for 6 hours under reflux using a water separator. After cooling, the mixture is. washed with a solution of NaHCO;, (5%) and with water and evaporated in vacuo. The residue is washed with a mixture of benzene and low boiling petroleum ether. The crystals'are filtered with suction, washed with the same. solvent and recrystal- 4 lized from methanol. The obtained l6-methylene-4-pregnene-17u-ol-3,20-dione (IV) melts at 223; ((2) 10.7 (chloroform) A 240-211 m Etta... 503

(C) 16 methylene 21-iod0-4-pregnen-17a-0l-3,20- di0ne.A solution of 15 g. of 16-methylene-4-pregnene- 17ot-ol-3,20-dione (IV) in a mixture of 225 ml. of tetrahydrofurane and 38 ml. of methanol is cooled to 4. With continuous stirring 22.5 g. of iodine are added in small portions taking care that the temperature does not rise above 1. Then NaOH (10%) is added drop- Wise until the color of the iodine has disappeared. About ml. of NaOH are required. The solution is poured into 3.5 l. of water, the precipitate is filtered with suction, washed with water and dried in vacuo at room temperature. 16-methylene-2l-iodo-4-pregnene-17a-ol-3 ,20-dione (V) is obtained.

(D) 1o-methylene-4-pw-egnene-17a,21-diol-3,20-di0ne 21 acetate.-The crude 21-iodide (V) is refluxed with 880 ml. of anhydrous acetone and 48 g. of potassium acetate for 18 hours. After evaporation of the solvent in vacuo the residue is washed with 500 ml. of water. The undissolved residue is filtered with suction, washed with water, dried and recrystallized from acetone. The l6-methylene-4-pregnene-17a,21-diol-3,20dione 21-acetate (VI) obtained melts at 162163, (a) +52 (chloroform).

(E) 16-methylene compound S.12 g. of 16-rnethylene 4-pregnene-17a,21-diol-3,20-dione-21-acetate (VI) are dissolved in 960 ml. of methanol. 480 ml. of a solution of KHCO (5%) are added. The solution is refluxed for three hours and then cooled. Crystals of 16- methylene-Reichsteins compound S separate which are purified by recrystallization from acetone, M.P. 205-207; (a) +47 (chloroform).

mer. 240 l;

If desired, the diester or mixed diester of compound VII can be prepared in known manner by reacting VI or VII with an acetylatin g or other acylating agent under the more rigorous conditions required for esterifying the tertiary 17a-hydroxyl group. Thus, the diacetate or mixed acetate-propionate or other combination of ester groups may be introduced into the lG-methylene Compound S.

In place of the direct iodination of the ZI-methyl group, such group can first be chlorinated or, preferably, bromi-- nated in known manner and the product so obtained then converted to the iodide by treatment with alkali metal iodide, or the chloride or bromide can be heated with the alkali metal hydroxide or organic salt to produce com-' pound VII or VI, respectively.

We claim:

1. The compound 2. In a process for the manufacture of 16-methy1ene-4- pregnene-l71z,2l-diol-3,20-dione and its esters, the stepswhich comprise reacting t,170t-OXldO-1-6/3-Il'l6thYl-4-Pl6gnene3,20-dione with. an acid to form 16-methylene-4-- pregnene-17a-ol-3,20-dione, halogenating the 21-methyl group, and reacting the product with a member of the group consisting of alkali metal hydroxides and onganic salts to produce a member of the group consisting of 16-' methylene-4-pregnene-17,21-diol-3,20-dione and the 21- ester thereof.

3. Process according to claim 2, including the step of dehydrogenating 16a,17a oxido-16fl-methyl-5-pregnene- 3B-ol-20-one by an Oppenauer reaction to form the 160i, 17a-oxido-16j8-methyl-4-pregnene-3,ZO-dione.

4. Process according to claim 2, including the step of reacting 16-methyl-4,16-pregnadiene-3,20-dione with an alkaline solution of hydrogen peroxide to form the 160:, 17a-oxido16/3-methyl-4-pregnene-3,20-di0ne.

5. Process according to claim 2, including the step of reacting 16-methyl-4,l6-pregnadiene-3,20-di0ne with an organic peracid.

6. Process according to claim 2, wherein the l6oz,l7ocoxido-l6B1methyl-4-pregnene-3,ZO-dion is heated with ptoluene-sulfonic acid in an inert solvent.

7. Process according to claim 2, wherein the 21-methyl group ishalogenated with an alkaline solution of iodine.

8. Process according to claim 2, wherein the halogenated intermediate is reacted with an alkali metal acetate to form the ZI-acetoxy derivative.

9. Process according to claim 8, including the step of saponifying the 21-acetate 'to yield the 16-methylene-4- pregnene-17a,21-diol-3,20-dione.

10. The compound 11. The compound omoooon;

12. A compound selected from the group consisting of a compound of the formula wherein R is selected from the group consisting of H and acetyl.

References Cited UNITED STATES PATENTS 2,878,247 3/1959 Miramontes et a1. 260239 2,686,181 8/1954 Julian et al 260-239 2,932,639 4/1960 Oliveto et a1. 260-239 3,296,075 1/ 1967 Kirk et a1. 167-74 ELBERT L. ROBERTS, Primary Examiner.

L. H. GASTON, M. LIEBMAN, I. MARCUS,

Examiners. H. A. FRENCH, Assistant Examiner. 

1. THE COMPOUND 